Regulation of the CNC-bZIP transcription factor Nrf2 by Keap1 and the axis between GSK-3 and β-TrCP

John D. Hayes (Lead / Corresponding author), Kimimuepigha Ebisine, Ritu S. Sharma, Sudhir Chowdhry, Albena T. Dinkova-Kostova, Calum Sutherland

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    Abstract

    The transcription factor NF-E2 p45-related factor 2 (Nrf2) mediates adaptation to oxidative stress by inducing cytoprotective genes including heme oxygenase-1 (HMOX1) and NAD(P)H:quinone oxidoreductase-1 (NQO1). Nrf2 is principally controlled by Kelch-like ECH-associated protein 1 (Keap1), which allows constitutive ubiquitylation and rapid degradation of Nrf2 by the cullin-3 (Cul3)-RING ubiquitin ligase CRLKeap1 under non-stressed conditions. Simultaneously, glycogen synthase kinase-3 (GSK-3) also negatively controls Nrf2 through phosphorylation of a DSGIS-containing destruction motif in Nrf2, which then allows binding by β-transducin repeat-containing protein (β-TrCP) and ubiquitylation of the transcription factor by the Skp1−Cul1−F-box (SCF) ubiquitin ligase designated SCFβ-TrCP. It is well documented that oxidative stressors activate Nrf2 by antagonizing Keap1. We now show that both tert-butyl hydroquinone (tBHQ) and diethyl maleate (DEM), but not sulforaphane, induce Hmox1 and Nqo1 in Keap1−/− mouse embryonic fibroblasts (MEFs). Moreover, expression of Hmox1 and Nqo1 in Keap1−/− MEFs is substantially blunted by inhibition of either phosphoinositide 3-kinase (PI3K, using LY294002) or protein kinase B (PKB/Akt, using MK-2206), whereas inhibition of GSK-3 (using CT99021) induces expression of Hmox1 and Nqo1. Herein, we provide evidence that Nrf2 is subject to repression by both Keap1 and the axis between GSK-3 and β-TrCP. One likely scenario is that loss of the phosphatidylinositol (3,4,5)-trisphosphate (PIP3) 3-phosphatase activity of PTEN caused by tBHQ and DEM results in an increase in the levels of PIP3 produced by PI3K, and hence 3-phosphoinositide-dependent protein kinase-1 (PDK1) activity, which then stimulates PKB/Akt signaling.

    Original languageEnglish
    Pages (from-to)92-103
    Number of pages12
    JournalCurrent Opinion in Toxicology
    Volume1
    Early online date8 Oct 2016
    DOIs
    Publication statusPublished - Dec 2016

    Fingerprint

    NF-E2-Related Factor 2
    Basic-Leucine Zipper Transcription Factors
    Glycogen Synthase Kinase 3
    diethyl maleate
    Fibroblasts
    Ligases
    Ubiquitin
    Phosphatidylinositol 3-Kinases
    NF-E2 Transcription Factor
    3-Phosphoinositide-Dependent Protein Kinases
    Proteins
    Cullin Proteins
    Transducin
    Ubiquitination
    Proto-Oncogene Proteins c-akt
    Phosphorylation
    Heme Oxygenase-1
    Oxidative stress
    Phosphatidylinositols
    Phosphoric Monoester Hydrolases

    Keywords

    • GSK-3
    • Keap1
    • Nrf2
    • PI3K
    • PKB/Akt
    • PTEN
    • β-TrCP

    Cite this

    @article{525f207fe290463a969ff1b8aaffd00c,
    title = "Regulation of the CNC-bZIP transcription factor Nrf2 by Keap1 and the axis between GSK-3 and β-TrCP",
    abstract = "The transcription factor NF-E2 p45-related factor 2 (Nrf2) mediates adaptation to oxidative stress by inducing cytoprotective genes including heme oxygenase-1 (HMOX1) and NAD(P)H:quinone oxidoreductase-1 (NQO1). Nrf2 is principally controlled by Kelch-like ECH-associated protein 1 (Keap1), which allows constitutive ubiquitylation and rapid degradation of Nrf2 by the cullin-3 (Cul3)-RING ubiquitin ligase CRLKeap1 under non-stressed conditions. Simultaneously, glycogen synthase kinase-3 (GSK-3) also negatively controls Nrf2 through phosphorylation of a DSGIS-containing destruction motif in Nrf2, which then allows binding by β-transducin repeat-containing protein (β-TrCP) and ubiquitylation of the transcription factor by the Skp1−Cul1−F-box (SCF) ubiquitin ligase designated SCFβ-TrCP. It is well documented that oxidative stressors activate Nrf2 by antagonizing Keap1. We now show that both tert-butyl hydroquinone (tBHQ) and diethyl maleate (DEM), but not sulforaphane, induce Hmox1 and Nqo1 in Keap1−/− mouse embryonic fibroblasts (MEFs). Moreover, expression of Hmox1 and Nqo1 in Keap1−/− MEFs is substantially blunted by inhibition of either phosphoinositide 3-kinase (PI3K, using LY294002) or protein kinase B (PKB/Akt, using MK-2206), whereas inhibition of GSK-3 (using CT99021) induces expression of Hmox1 and Nqo1. Herein, we provide evidence that Nrf2 is subject to repression by both Keap1 and the axis between GSK-3 and β-TrCP. One likely scenario is that loss of the phosphatidylinositol (3,4,5)-trisphosphate (PIP3) 3-phosphatase activity of PTEN caused by tBHQ and DEM results in an increase in the levels of PIP3 produced by PI3K, and hence 3-phosphoinositide-dependent protein kinase-1 (PDK1) activity, which then stimulates PKB/Akt signaling.",
    keywords = "GSK-3, Keap1, Nrf2, PI3K, PKB/Akt, PTEN, β-TrCP",
    author = "Hayes, {John D.} and Kimimuepigha Ebisine and Sharma, {Ritu S.} and Sudhir Chowdhry and Dinkova-Kostova, {Albena T.} and Calum Sutherland",
    note = "We gratefully acknowledge the Medical Research Council for their financial support (MR/N009851/1).",
    year = "2016",
    month = "12",
    doi = "10.1016/j.cotox.2016.10.003",
    language = "English",
    volume = "1",
    pages = "92--103",
    journal = "Current Opinion in Toxicology",
    issn = "2468-2020",
    publisher = "Elsevier",

    }

    TY - JOUR

    T1 - Regulation of the CNC-bZIP transcription factor Nrf2 by Keap1 and the axis between GSK-3 and β-TrCP

    AU - Hayes, John D.

    AU - Ebisine, Kimimuepigha

    AU - Sharma, Ritu S.

    AU - Chowdhry, Sudhir

    AU - Dinkova-Kostova, Albena T.

    AU - Sutherland, Calum

    N1 - We gratefully acknowledge the Medical Research Council for their financial support (MR/N009851/1).

    PY - 2016/12

    Y1 - 2016/12

    N2 - The transcription factor NF-E2 p45-related factor 2 (Nrf2) mediates adaptation to oxidative stress by inducing cytoprotective genes including heme oxygenase-1 (HMOX1) and NAD(P)H:quinone oxidoreductase-1 (NQO1). Nrf2 is principally controlled by Kelch-like ECH-associated protein 1 (Keap1), which allows constitutive ubiquitylation and rapid degradation of Nrf2 by the cullin-3 (Cul3)-RING ubiquitin ligase CRLKeap1 under non-stressed conditions. Simultaneously, glycogen synthase kinase-3 (GSK-3) also negatively controls Nrf2 through phosphorylation of a DSGIS-containing destruction motif in Nrf2, which then allows binding by β-transducin repeat-containing protein (β-TrCP) and ubiquitylation of the transcription factor by the Skp1−Cul1−F-box (SCF) ubiquitin ligase designated SCFβ-TrCP. It is well documented that oxidative stressors activate Nrf2 by antagonizing Keap1. We now show that both tert-butyl hydroquinone (tBHQ) and diethyl maleate (DEM), but not sulforaphane, induce Hmox1 and Nqo1 in Keap1−/− mouse embryonic fibroblasts (MEFs). Moreover, expression of Hmox1 and Nqo1 in Keap1−/− MEFs is substantially blunted by inhibition of either phosphoinositide 3-kinase (PI3K, using LY294002) or protein kinase B (PKB/Akt, using MK-2206), whereas inhibition of GSK-3 (using CT99021) induces expression of Hmox1 and Nqo1. Herein, we provide evidence that Nrf2 is subject to repression by both Keap1 and the axis between GSK-3 and β-TrCP. One likely scenario is that loss of the phosphatidylinositol (3,4,5)-trisphosphate (PIP3) 3-phosphatase activity of PTEN caused by tBHQ and DEM results in an increase in the levels of PIP3 produced by PI3K, and hence 3-phosphoinositide-dependent protein kinase-1 (PDK1) activity, which then stimulates PKB/Akt signaling.

    AB - The transcription factor NF-E2 p45-related factor 2 (Nrf2) mediates adaptation to oxidative stress by inducing cytoprotective genes including heme oxygenase-1 (HMOX1) and NAD(P)H:quinone oxidoreductase-1 (NQO1). Nrf2 is principally controlled by Kelch-like ECH-associated protein 1 (Keap1), which allows constitutive ubiquitylation and rapid degradation of Nrf2 by the cullin-3 (Cul3)-RING ubiquitin ligase CRLKeap1 under non-stressed conditions. Simultaneously, glycogen synthase kinase-3 (GSK-3) also negatively controls Nrf2 through phosphorylation of a DSGIS-containing destruction motif in Nrf2, which then allows binding by β-transducin repeat-containing protein (β-TrCP) and ubiquitylation of the transcription factor by the Skp1−Cul1−F-box (SCF) ubiquitin ligase designated SCFβ-TrCP. It is well documented that oxidative stressors activate Nrf2 by antagonizing Keap1. We now show that both tert-butyl hydroquinone (tBHQ) and diethyl maleate (DEM), but not sulforaphane, induce Hmox1 and Nqo1 in Keap1−/− mouse embryonic fibroblasts (MEFs). Moreover, expression of Hmox1 and Nqo1 in Keap1−/− MEFs is substantially blunted by inhibition of either phosphoinositide 3-kinase (PI3K, using LY294002) or protein kinase B (PKB/Akt, using MK-2206), whereas inhibition of GSK-3 (using CT99021) induces expression of Hmox1 and Nqo1. Herein, we provide evidence that Nrf2 is subject to repression by both Keap1 and the axis between GSK-3 and β-TrCP. One likely scenario is that loss of the phosphatidylinositol (3,4,5)-trisphosphate (PIP3) 3-phosphatase activity of PTEN caused by tBHQ and DEM results in an increase in the levels of PIP3 produced by PI3K, and hence 3-phosphoinositide-dependent protein kinase-1 (PDK1) activity, which then stimulates PKB/Akt signaling.

    KW - GSK-3

    KW - Keap1

    KW - Nrf2

    KW - PI3K

    KW - PKB/Akt

    KW - PTEN

    KW - β-TrCP

    UR - http://www.scopus.com/inward/record.url?scp=85016789450&partnerID=8YFLogxK

    U2 - 10.1016/j.cotox.2016.10.003

    DO - 10.1016/j.cotox.2016.10.003

    M3 - Review article

    AN - SCOPUS:85016789450

    VL - 1

    SP - 92

    EP - 103

    JO - Current Opinion in Toxicology

    JF - Current Opinion in Toxicology

    SN - 2468-2020

    ER -